This proposal outlines a comprehensive research program directed toward the synthesis of compounds of demonstrated or potential importance in cancer research/treatment. The synthetic component of this effort emphasizes the development of new methods and strategies for many-membered ring synthesis, fused-ring synthesis, and cannabinoid synthesis. A continuation of our olefin metathesis studies is designed to provide a general solution to the synthesis of germacradienes, a natural product class membered by various antitumor agents. The viability of a macro-expansion method designed to service the antitumor lankacidins and lathyranes will also be evaluated. An expansion/fragmentation method for many-membered ring synthesis will be directed initially at a methymycin synthesis. A continuation of our studies on the olefin metathesis/transannular ene method for fused ring synthesis will be directed at the synthesis of the cytotoxic agents warburganal and muzigadial. Intramolecular homo-Diels-Alder and arene-olefin cycloadditions will be studied in connection with syntheses of antitumor pseudoguaianes. The latter method will also be explored in connection with syntheses in the pentalenolactone and coriolin series including the antitumor agent coriolin. A new enolate chemistry will be developed in connection with a general approach to cannabinoid synthesis.